Identification Of Erbb4 Mutant Alleles That Function As Tumor Drivers.

Abstract Introduction: ERBB4 (HER4) is a member of the ERBB family of receptor tyrosine kinases, which includes the epidermal growth factor receptor (EGFR/ERBB1/HER1), ERBB2 (Neu/HER2), and ERBB3 (HER3). EGFR and ERBB2 are well-validated targets in a variety of solid tumors. In contrast, the roles that ERBB4 plays in human tumors are less well defined. Nonetheless, it is accepted that ERBB4 homodimers function as tumor suppressors and ERBB4 heterodimers function as oncogenes. Moreover, our in silico analyses of The Cancer Genome Atlas - Skin Cutaneous Melanoma dataset suggest that ERBB4 mutant alleles function as drivers of BRAF WT metastatic melanomas. Furthermore, ERBB2-ERBB4 heterodimers are associated with elevated tumor proliferation in pediatric ependymomas. Thus, here we describe model systems that we are using to identify ERBB4 gain-of-function (GOF) mutant alleles that stimulate the oncogenic activity of ERBB4-ERBB2 or ERBB4-EGFR heterodimers, as well as ERBB4 loss-of-function (LOF) mutant alleles that disrupt the tumor suppressor activity of ERBB4 homodimers. Experimental Procedures: In the 32D mouse myeloid cell line, ERBB4 homodimers inhibit cell proliferation, whereas ERBB4-ERBB4 heterodimers stimulate cell proliferation. Moreover, we have obtained seven human melanoma cell lines that possess WT BRAF. In these model systems we will express known GOF ERBB4 mutants (Y285C, D595V, Q646C, D931Y, K935I), known LOF ERBB4 mutants (V673I, K751M, G802dup, D861Y, R927Q, R1275W, Y1056F, Ct-b) and ERBB4 mutants found in melanoma samples (R106C, E452K, R711C, P759L, D813N, D861N, R992C). We will evaluate the effects of these ERBB4 mutants on cell proliferation, anchorage-independence, and motility. Data Summary: We anticipate that we will identify GOF ERBB4 mutant alleles that stimulate the oncogenic activity of ERBB4 heterodimers and LOF ERBB4 mutant alleles that disrupt the tumor suppressor activity of ERBB4 homodimers. By evaluating these mutants in the context of human melanoma cell lines, we anticipate that we will identify ERBB4 mutant alleles that function as bona fide tumor drivers. Conclusion: ERBB4 appears to be important to the genesis and/or progression of several types of cancer. However, the fact that ERBB4 functions as a context-dependent oncogene and tumor suppressor gene poses a unique challenge to the identification of driver mutant alleles. The development of the model systems that we present here is an invaluable step forward in the study of ERBB4 as a driver of cancer genesis and/or progression. Citation Format: Lauren Lucas, Vipasha Dwivedi, Joely Burgess, Connor Kelley, Elizabeth Knerr, Jessica Markham, Stephen Miller, David Riese. Identification of ERBB4 mutant alleles that function as tumor drivers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 814.